We have previously reported that during the catalytic cycle of rat liver cytochrome P-450 in vitro that the prosthetic heme group is destroyed and its degradation products become irreversibly bound to microsomal proteins. The mechanism of this degradation process also appeared to be intimately linked to cellular lipid peroxidation, since more degradation occurred when microsomes were incubated with carbon tetrachloride or with linoleic hydroperoxide, which initiate lipid peroxidation. We now report that the heme-derived degradation products found in vitro are preferentially bound to cytochrome P-450. Moreover, a similar degradation process also takes place after the administration of carbon tetrachloride to rats and it appears to result in the rapid loss of immunoreactive cytochrome P-450 from liver microsomes. These results suggest that the bound heme degradation products have 'tagged' the cytochrome P-450 adducts for catabolism by cellular proteases. If other xenobiotics cause similar effects, this may have general importance in the regulation of the activity of this important family of enzymes that not only metabolize foreign compounds, but also endogenous substrates such as steroids, prostaglandins, leucotrienes, and fatty acids.